Biology subjects

Gombos, M.

Publications and source records attributed to Gombos, M..

6 recordsLinked to original sources

bioRxiv2026

Arabidopsis RETINOBLASTOMA-RELATED controls cell size during plant development in a dose-dependent manner

The RETINOBLASTOMA-RELATED (RBR) protein in plants functions as a cell-cycle inhibitor, regulating cell numbers in developing organs and establishing cellular quiescence during growth. Although the role of RBR counterparts in animals also involves regulating cell size, this potential function remains unexplored in plants. We investigated transgenic Arabidopsis plants with altered RBR levels and observed corresponding changes in cell size from embryogenesis through organ development. In addition, stomatal meristemoid cells with reduced RBR levels divided beyond the size threshold, whereas elevated RBR levels increased their size. RBR stimulated terminal differentiation in the stomatal lineage by inducing MUTE and CYCLIN D5;1 expression, whereas reduced RBR levels maintained asymmetric divisions through high SPEECHLESS and CYCLIN D3;1 expression. Interestingly, the cell proliferation-dependent phosphorylation of RBR at the conserved 911Ser site positively correlated with RBR protein levels in the transgenic lines and aligned with the effect of RBR on cell size. This study discusses the potential link between RBRs control of cell proliferation and cell size, providing new insights into the coordinated regulation of plant development.

plant biology↗

bioRxiv2026

Redundant roles of YES and SRC tyrosine kinases in driving malignant peripheral nerve sheath tumors

Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive soft tissue sarcomas that are largely incurable with no clinically effective systemic therapies or immunotherapies for advanced disease. Here, we identify the SRC-family kinases (SFKs) YES and SRC as redundant, essential drivers of MPNST growth. Dual inhibition of YES/SRC activity by genetic silencing or pharmacological SFK inhibitors markedly suppressed the proliferation of multiple NF1-mutant MPNST cell lines. In vivo, conditional genetic depletion of YES/SRC in MPNST cells abrogated tumor growth in subcutaneous and orthotopic models, and dasatinib treatment delayed tumor progression and improved overall survival. Integrated transcriptomic and phosphotyrosine proteomic analyses revealed that YES/SRC inactivation extensively rewires MPNST signaling, coordinately repressing multiple oncogenic signaling pathways and downstream cell cycle transcriptional programs. Unexpectedly, YES/SRC inhibition also upregulated interferon and antigen processing and presentation pathways and increased cell-surface MHC class I expression, consistent with tumor-intrinsic immune reactivation. Clinically, analysis of a large sarcoma cohort demonstrated that YES1 is significantly overexpressed in MPNST compared to benign soft tissue tumors. Collectively, our findings establish YES/SRC as non-oncogene vulnerabilities in MPNST.

cancer biology↗

bioRxiv2026

Complex regulation of RETINOBLASTOMA-RELATED's interactions with E2Fs via phosphorylation

Arabidopsis RETINOBLASTOMA-RELATED (RBR) regulates cell proliferation by interacting with E2F transcription factors and DIMERIZATION PARTNER, RB-LIKE, E2F AND MULTI-VULVAL CLASS B COMPLEX (DREAM) components. Although CDK-CYCD phosphorylation is believed to affect RBRs E2F-binding capacity, the precise phosphorylation events inhibiting RBRs cell cycle function remain unclear. This study found RBR phosphorylated at 13 of 16 CDK sites in Arabidopsis, with many phosphorylated forms still binding E2Fs. In contrast, multi-phosphorylated RBR forms with phosphorylated 911S site in Arabidopsis thaliana and corresponding sites in Medicago truncatula or Brassica napus do not co-purify with E2Fs and DREAM components but interact with RNA-binding proteins involved in post-transcriptional regulation through ribosomal biogenesis and protein translation. The 911S phosphorylation is high in proliferating cells and rapidly diminishes under DNA damage conditions, indicating its role in switching from proliferation to quiescence under stress. However, molecular modelling implies that this site is not accessible for phosphorylation if RBR is in complex with E2Fs. These findings suggest that different phosphorylation events inhibit RBRs capacity to form complexes with E2Fs and to release E2Fs from RBR inhibition. We posit that multi-site phosphorylation coupled to 911S impedes free RBRs binding to E2Fs and DREAM components, but this is not the initial inhibitory phosphorylation contributing to the disruption of RBR-E2F-DP complexes. Rather, it facilitates RBR interaction with proteins involved in post-transcriptional cell cycle regulation.

plant biology↗

bioRxiv2024

Retinoblastoma-related (RBR) has both canonical and non-canonical regulatory functions during thermo-morphogenic responses in Arabidopsis seedlings

Warm temperatures accelerate plant growth, but the underlying molecular mechanism is not fully understood. Here, we show that increasing the temperature from 22{degrees}C to 28{degrees}C rapidly activates proliferation in the apical shoot and root meristems of wild-type Arabidopsis seedlings. We found that one of the central regulators of cell proliferation, the cell cycle inhibitor RETINOBLASTOMA-RELATED (RBR), is suppressed by warm temperatures. RBR became hyper-phosphorylated at a conserved CYCLIN-DEPENDENT KINASE (CDK) site in young seedlings growing at 28{degrees}C, in parallel with the stimulation of the expressions of the regulatory CYCLIN D/A subunits of CDK(s). Interestingly, while under warm temperatures ectopic RBR slowed down the acceleration of cell proliferation, it triggered elongation growth of post-mitotic cells in the hypocotyl. In agreement, the central regulatory genes of thermomorphogenic response, including PIF4 and PIF7, as well as their downstream auxin biosynthetic YUCCA genes (YUC1-2 and YUC8-9) were all up-regulated in the ectopic RBR expressing line but down-regulated in a mutant line with reduced RBR level. We suggest that RBR has both canonical and non-canonical functions under warm temperatures to control proliferative and elongation growth, respectively.

plant biology↗

bioRxiv2022

The canonical E2Fs together with RETINOBLASTOMA-RELATED are required to establish quiescence during plant development

Maintaining stable and transient quiescence in differentiated and stem cells, respectively, requires repression of the cell cycle. The plant RETINOBLASTOMA-RELATED (RBR) has been implicated in stem cell maintenance, presumably by forming repressor complexes with E2F transcription factors. Surprisingly we find that mutations in all three canonical E2Fs do not compromise the cell cycle, but similarly to RBR silencing, result in overproliferation. Contrary to the growth arrest upon RBR silencing, when exit from proliferation to differentiation is inhibited, the e2fabc mutant develops enlarged organs with supernumerary stem and differentiated cells as the quiescence is compromised. While E2F, RBR and the M-phase regulatory MYB3Rs are part of the DREAM repressor complexes, and recruited to overlapping groups of targets, they regulate distinct sets of genes. Only the loss of E2Fs but not the MYB3Rs interferes with quiescence, which might be due to the ability of E2Fs to control both G1-S and some key G2-M targets. We conclude that collectively the three canonical E2Fs in complex with RBR have central roles in establishing cellular quiescence during organ development, leading to enhanced plant growth.

plant biology↗

bioRxiv2021

A hierarchical transcriptional network activates specific CDK inhibitors that regulate G2 to control cell size and number in Arabidopsis

How cell size and number are determined during organ development remains a fundamental question in cell biology. Here, we identified a GRAS family transcription factor, called SCARECROW-LIKE28 (SCL28), with a critical role in determining cell size in Arabidopsis. SCL28 is part of a transcriptional regulatory network downstream of the central MYB3Rs that regulate G2 to M phase cell cycle transition. We show that SCL28 forms a dimer with the AP2-type transcription factor, AtSMOS1, which defines the specificity for promoter binding and directly activates transcription of a specific set of SIAMESE-RELATED (SMR) family genes, encoding plant-specific inhibitors of cyclin-dependent kinases and thus inhibiting cell cycle progression at G2 and promoting the onset of endoreplication. Through this dose-dependent regulation of SMR transcription, SCL28 quantitatively sets the balance between cell size and number without dramatically changing final organ size. We propose that this hierarchical transcriptional network constitutes a cell cycle regulatory mechanism that allows to adjust cell size and number to attain robust organ growth.

plant biology↗